In vitro lymphocyte dysfunction in Hodgkin's disease.

In vitro lymphocyte function and delayed cutaneous hypersensitivity (DCH) response in vivo were assessed in 27 patients with Hodgkin's disease. Lymphocyte responsiveness to phytohemagglutinin (PHA) and to a standard mitomycin C-treated lymphoblastoid cell line in a one-way mixed lymphocyte culture (MLC) was measured simultaneously and compared to that of controls. Seventeen patients, including 6 of 11 untreated patients, had some defect either of DCH or of an in vitro lymphocyte function. In patients lacking a DCH response, the PHA and MLC responses were significantly depressed as compared to either those with intact DCH or normal controls. In patients with intact DCH, the PHA but not the MLC response was significantly depressed. PHA stimulation and MLC may define different subpopulations of responding thymus-derived lymphocytes in patients with Hodgkin's disease. Measurement of lymphocyte response to PHA and to a standard lymphoblastoid cell line in the one-way MLC may provide complementary in vitro means of assessing cell-mediated immunity in patients with Hodgkin's disease.

Autologous bone marrow transplantation in patients with cancer.

Ten patients with non-leukemic neoplasms received intensive, marrow-lethal doses of drugs and radiation followed by rescue with autologous cryopreserved bone marrow (nine) or marrow from an identical twin as part of a phase 1-2 study. Nine patients had extensive disease that was unresponsive to conventional therapy. Marrow engraftment was documented in all evaluable cases and most patients had a substantial anti-tumor response. Three patients are alive from 4 to 10 months following transplantation without evidence of disease.

Chronic graft versus host disease: a syndrome of disordered immunity.

A chronic, debilitating syndrome related to graft-versus-host disease (GVHD) has been recognized in long-term survivors following allogeneic bone marrow transplantation. In six of 20 marrow graft recipients who survived for more than one year after receiving a transplant, this complication developed; they were studied to better define the syndrome. There was no association between the sex of either donor or recipient, HLA type, blood group, conditioning regimen or marrow cell dose and subsequent development of chronic GVHD. All six patients had mild to moderate manifestations of acute GVHD following prompt engraftment. Chronic GVHD was characterized in each patient by progression to scleroderma-like skin involvement with hyperkeratosis, reticular hyperpigmentation, atrophy with ulceration and fibrosis with limitation of joint movement. A sicca syndrome was prominent in five patients. Four patients had idiopathic interstitial pneumonitis. Infectious complications were frequent, and DNA viral infections were prominent. Autoimmune hemolytic anemia was present in three patients, and one patient had antinuclear antibody (ANA). A spectrum of immune abnormalities was observed including hypergammaglobulinemia, immunoglobulin M (IgM) paraprotein, elevated circulating immune complexes, plasma cell hyperplasia, lymphocytotoxic antibodies and autoantibodies to autologous or donor lymphocytes. Despite clinical similarity to collagen vascular diseases, none of these patients had anti-DNA antibodies or antibodies to smooth muscle, thyroid or extractable nuclear antigens. In one patient, a skin graft from the marrow donor remained healthy despite progressive involvement in recipient skin, whereas unrelated skin grafts were rejected. Immunosuppressive therapy and plasmapheresis have not been effective. Four patients have died (median survival 458 days from transplantation). Chronic GVHD appears to be a syndrome of disordered immune regulation features of immunodeficiency and autoimmunity.

High-dose combined-modality therapy and autologous bone marrow transplantation in resistant cancer.

Fourteen patients with resistant cancers received high-dose chemotherapy and total body irradiation followed by rescue with autologous cryopreserved bone marrow cells. In seven patients, disease has remained in remission for periods up to two years. These data indicate that effectiveness of high-dose combined-modality therapy and bone marrow autotransplantation in patients with resistant cancer. The high incidence of non-marrow toxicity may be reduced by the use of this modality before patients have received extensive therapy.

Emergence of a cell line with extreme hypodiploidy in blast crisis of chronic myelocytic leukemia.

Cytogenetic studies in a patient with chronic myelocytic leukemia (CML) demonstrated the emergence of an extremely hypodiploid cell line at the time of blast crisis, a modal chromosome number of 35, with the modal karyotype 35,XY, -3, -4, -5, -7, -9, -11, -12, -13, -15, -16, -17, -19, -20, -22, + t(9;22) (q34;q11, + Mar1, + Mar2, + Mar3. Giemsa-banding confirmed complex chromosome rearrangements and demonstrated distinct banding patterns for the marker chromosomes. Cytologic characteristics of the leukemia blasts were predominantly myeloid. There was no important clinical response to chemotherapy, including vincristine and prednisone, or to radiotherapy.

Infection of human and rhesus lymphoblastoid cells with Herpesvirus macaca.

The interaction between Herpesvirus macaca and lymphoblastoid cells grown in continuous culture, or purified from rhesus blood, was studied as a model for latent or chronic herpesvirus infection of leukocytes. Continuous lymphoblastoid cell lines infected in vitro were PA3, a human cell line with bone-marrow derived (B)-lymphocyte characteristics; LM/DM, a rhesus cell line with B-lymphocyte characteristics; and MOLT-4, a human cell line with thymus-derived (T)-lymphocyte characteristics. A distinct pattern of interaction was found for each lymphoblastoid cell line. A small but stable fraction of cells continued to express virus-specific antigens for more than three weeks following infection of the B-type lymphoblastoid cell lines of rhesus and human origin. Herpesvirus macaca replicated only in PA3 cells. Viral replication did not occur and viral antigens were not detected in either peripheral lymphocytes or MOLT-4 cells. The observations suggest that Herpesvirus macaca interacts in distinct patterns with different lymphoid cell lines in vitro, and that within a given culture, subpopulations of lymphoid cells are present at a given time which respond to the virus differently.

Systemic therapy for metastatic breast cancer.

The data reviewed in this conference suggest that initial therapeutic decisions for patients with metastic breast cancer be based on the presence or absence of an estrogen receptor in the tumor. Patients with estrogen receptor in their original primary breast cancer or in a subsequent metastitic lesion are candidates for hormonal manipulation, whereas patients lacking estrogen receptor in their tumor are treated for their metastic disease with nonhormonal chemotherapy. Nonhormonal therapy usually consists of a combination of cytotoxic drugs including cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Other programs of combination chemotherapy are under active study, especially programs that include nonspecific immune stimulation with Corynebacterium parvum or bacillus Calmette-Guérin (BCG). Inasmuch as patients with Stage II primary breast cancer frequently have "micrometastatic" disease, combination chemotherapy is also under study as an adjuvant to surgery. Preliminary results strongly support the use of such therapy.

Electron-microscopic study of Herpesvirus macaca in human fibroblasts.

An electron microscopic study of the morphology of Herpesvirus macaca, a serologically distinct infectious agent isolated from the leukocytes of rhesus monkeys, was performed. WI-38 fibroblast monolayers were infected with the virus and examined 18 days later. The morphology of Herpesvirus macaca was, in general, typical of the herpesvirus group. Enveloped virus particles observed via negative-stain technique had a diameter of 145-155 nm. An inner capsid composed of hexagonal capsomeres had a diameter of 100-110 nm and surrounded a central core. While enveloped forms appeared to be present within the nuclei of infected cells, they were not found in the cytoplasm except within vacuolar structures. Associated changes were found in the morphology of infected cells, including intracytoplasmic myelin figures.

Comparative trial of influenza vaccines. I. Immunogenicity of whole virus and split product vaccines in man.

Groups of about 100 persons aged 6 to 88 years were given 1 of 6 commercially prepared whole virus or split-product bivalent (A/England-B/Mass) influenza vaccines and 6 weeks later were given 1 of 5 monovalent (B/Hong Kong) vaccines. Hemagglutination-inhibiting (HI) antibody titers in serum specimens taken 6 and 12 weeks after inoculation were compared to those obtained before immunization. Overall antibody responses in all groups were adequate, yielding HI titers that are associated with relatively good levels of protection from infection. No differences were noted among the vaccines in their ability to boost pre-existing antibody. The tributyl phosphate (TBP) split-product vaccine, however, induced significantly lower homologous seroconversion and geometric mean antibody titers (GMT) to A/England and heterologous antibody titers to A/Aichi in persons without pre-existing antibody than did equivalent whole virus vaccines. Both the TBP and the ether-treated monovalent B/Hong Kong vaccines also induced lower heterologous GMT's to B/Mass in initially seronegative individuals. These data agree with previous observations that the primary response to influenza and other viral vaccines prepared from disrupted virions results in lower levels of antibody than does that to equivalent whole virus preparations. Studies are underway to determine whether the lesser immune response induced by these vaccines in seronegative persons is the result of smaller amounts of antigen in such preparations or because the antigen may be processed less efficiently by humoral or cellular immune mechanisms.

Bone-marrow transplantation in acute leukaemia.

Survival in 33 patients with resistant leukaemia treated by marrow transplantation was compared with that of 37 matched patients treated by conventional and experimental chemotherapy. All patients in the transplant group were rendered free of detectable leukaemia for periods of from 36 days to more than 2 1/2 years, while only 6 patients in the chemotherapy group achieved a haematological remission. Overall survival in both groups was poor; however, 5 patients (15%) in the transplant group remain alive and in haematological remission 1--2 1/2 years after transplantation, while no patient in the chemotherapy group survived longer than 13 months. Bone-marrow transplantation appears to offer a small but distinct possibility of long-term survival in patients with acute leukaemia resistant to conventional therapy.